While much attention has been paid to changes in transcription, the regulation of protein synthesis has only recently been recognized as an important contributor to nociceptive plasticity (Price and Geranton, 2009). Control of gene expression at the level of translation affords DRG neurons a rapid and local mechanism through which to generate new proteins involved in the amplification of nociceptive signaling. We hypothesize that algogenic compounds engage signaling to the translational machinery in nociceptors and their axons to enhance the efficiency of the rate-limiting step of translation, elongation initiation. This would lead to the rapid, de-novo synthesis of proteins that can mediate acute sensitization and act as positive retrograde signals to elicit long-lasting changes in gene expression sustaining sensitization. Our preliminary findings indicate that the pro-nociceptive cytokine, interleukin 6 (IL-6), stimulates translation-mediated changes in gene expression in DRG neurons via activation of the ERK-MNK pathway which phosphorylates and activates the eIF4E elongation initiation complex. We also show that IL-6 leads to CREB protein synthesis via this pathway suggesting that this transcription factor may act as a positive retrograde signal to the cell body linking local IL-6 effects in the periphery to transcriptional changes in the nucleus sustaining long- term sensitization of these neurons. In this proposal we will address the following questions through our specific aims: 1) How does IL-6 signal to the translation machinery in DRG neurons? 2) Does IL-6 stimulate translation within the axonal compartment to generate retrograde signaling to the neuronal nucleus? 3) What is the role of IL-6-mediated translation control in IL-6-induced acute and latent nociceptor sensitization in vivo? The proposed research will provide essential information on mechanisms of IL-6-induced translation regulation in DRG neurons and their axons leading to nociceptor sensitization, potentially unveiling new mechanisms and new targets for the management of chronic pain.
Chronic pain is a major clinical problem with significant barriers to treatment. Changes in gene expression upon injury or disease are known causes for the chronification of pain but mechanisms underlying these effects are poorly understood. Through this research, we intend to discover novel mechanisms of regulation of gene expression, linked to translation control, which will enhance our understanding of how pain becomes chronic and potentially lead to the discovery of novel treatment avenues.
|Moy, Jamie K; Khoutorsky, Arkady; Asiedu, Marina N et al. (2017) The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain. J Neurosci 37:7481-7499|
|Sahn, James J; Mejia, Galo L; Ray, Pradipta R et al. (2017) Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice. ACS Chem Neurosci 8:1801-1811|
|Li, Xiuying; Che, Zifan; Mazhar, Khadijah et al. (2017) Ultrafast Near-Infrared Light-triggered Intracellular Uncaging to Probe Cell Signaling. Adv Funct Mater 27:|
|Burton, Michael D; Tillu, Dipti V; Mazhar, Khadijah et al. (2017) Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice. Neuroscience 359:119-129|
|Hanamura, Kenji; Washburn, Halley R; Sheffler-Collins, Sean I et al. (2017) Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain. PLoS Biol 15:e2002457|
|Park, Sung Il; Shin, Gunchul; McCall, Jordan G et al. (2016) Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics. Proc Natl Acad Sci U S A 113:E8169-E8177|
|Asiedu, Marina N; Dussor, Gregory; Price, Theodore J (2016) Targeting AMPK for the Alleviation of Pathological Pain. EXS 107:257-285|
|Burgos-Vega, Carolina C; Quigley, Lilyana D; Avona, Amanda et al. (2016) Dural stimulation in rats causes brain-derived neurotrophic factor-dependent priming to subthreshold stimuli including a migraine trigger. Pain 157:2722-2730|
|Pember, Stephen O; Mejia, Galo L; Price, Theodore J et al. (2016) Piperidinyl thiazole isoxazolines: A new series of highly potent, slowly reversible FAAH inhibitors with analgesic properties. Bioorg Med Chem Lett 26:2965-2973|
|Davidson, Steve; Golden, Judith P; Copits, Bryan A et al. (2016) Group II mGluRs suppress hyperexcitability in mouse and human nociceptors. Pain 157:2081-8|
Showing the most recent 10 out of 56 publications